The present invention relates to a method of synthesizing 1H-indazole compounds, and more particularly, to a method which utilizes mild operating conditions to react aromatic carbonyl compounds with a nitrogen source to form oximes which are converted to 1H-indazoles.
Indazoles, and particularly, 1H-indazoles, form the core structures of many diverse pharmaceutical products. For example, 1H-indazoles may be used in anti-cancer, fertility, arthritic, anti-inflammatory and contraceptive pharmaceutical products. In addition, 1H-indazoles have demonstrated activity as HIV protease inhibitors, and 5-HT3 antagonists. As a result, it has become increasingly desirable to be able to develop safe and efficient methods of producing indazoles.
1H-indazole compounds are typically synthesized under harsh conditions which include the use of strong acids, strong bases, or high temperatures. More recent methods have involved the use of metals, which are undesirable, or have produced indazoles having limited product scope.
Other recent approaches to the synthesis of 1H-indazole compounds are shown in scheme 1 below and include the addition of hydrazine to fluorobenzaldehydes.

However, the scope of this reaction is limited to the use of fluorobenzaldehydes and does not allow substitution at the 3-position.
The palladium-catalyzed synthesis of indazoles from hydrazones requires a high catalyst loading of palladium and provides only a tosyl-protected type of indazole. The Nichols method may also be used to make indazoles, but requires long reaction times, high temperatures and CO pressure, and an iron catalyst. The CuO catalyzed method provides only methyl-protected type indazoles, and the yields are low.
More recently, the synthesis of indazoles has been achieved via 1,3-dipolar cycloaddition reactions of arynes and diazomethane derivatives. See Jin et al., “An Efficient, Facile, and General Synthesis of 1H-Indazoles by 1,3-dipolar Cycloaddition of Arynes with Diazomethane Derivatives, Angew. Chem. Int. Ed., 2007, 46, 3323-3325.
However, the limited substrate scope, and in some instances, impractical conditions used in the current methods, demonstrates the need for a more general method of synthesizing indazoles.
Accordingly, there is still a need in the art for a method of synthesizing 1H-indazole compounds for use in pharmaceutical and other applications.